Professor Zhang Huilai: Theory and practice of PD-1 monoclonal antibody combination therapy in the field of hematology and tumors

In recent years, immune checkpoint inhibitors have become a treatment option for different cancer types
.

Today's immunotherapy in the field of hematological tumors mainly includes four modes: immune checkpoint inhibitors, bispecific antibody BITE, antibody drug conjugates (ADC), and CAR-T therapy
.

Among them, PD-1/PD-L1 plays a key role in the process of antigen presentation and antigen killing
.

PD-1/PD-L1 is involved in the immune escape mechanism of tumors
.

In 2020, Blood magazine published a study that classified different B-cell lymphomas into immuno-inflammatory and non-immuno-inflammatory based on genetic characteristics and response to immunotherapy
.

Among them, the immuno-inflammatory type is more sensitive to immunotherapy, including cHL, PMBL, C1 DLBCL and so on
.

Survival differences of different subtypes of DLBCL Although the current immunotherapy has made certain breakthroughs in anti-tumor, the occurrence of drug resistance is still inevitable
.

Regarding the drug resistance mechanism, an article published in Cancer Cell in 2020 combed the drug resistance mechanism of immunotherapy and found that the tumor antigen presentation process was destroyed, the INF-γ sensitivity was lost, the neoantigen was cleared, tumor-mediated immunosuppression, and others Activation of immune checkpoint pathways may be one of the mechanisms of drug resistance
.

At the same time, the resistance mechanism of PD-L1 is different in different subtypes of lymphoma
.

From the results of the study of PD-1 monoclonal antibody in the treatment of various lymphoma subtypes, in addition to cHL, PD-1 monoclonal antibody still has room for improvement in the ORR of various lymphoma subtypes
.

Current clinical studies have shown that the CR rate of PD-1 monoclonal antibody treatment is still low, and it is necessary to explore combined treatment options
.

The direction of immunotherapy combination, how to combine? At present, combination therapy is a trend, but we still need to explore who we will combine with
.

For example, the combination with other immune checkpoint inhibitors, and the combination with radiotherapy, other immunomodulatory drugs, cellular immunotherapy, targeted drugs, etc.
are all possible joint directions
.

1.
Immune checkpoint inhibitors combined with epigenetic drugs.
It is now known that epigenetic drugs play a role in immune response: increase the expression of tumor-associated antigens and MHC molecules; increase the production of antigen-presenting cells; enhance T cells to tumors Microenvironment migration; targeting apparent regulatory factors to restore T cell activation
.

Basic research has confirmed that the combination of HDAC inhibitors and PD-1 can increase the ratio of CD8+T/Treg numbers and inhibit MDSC function
.

In short, the synergistic effect of epigenetic modulation drugs and immunotherapy can improve the recognition of tumors
.

The latest results of Professor Han Weidong’s team exploring low-dose decitabine combined with carrelizumab in the treatment of R/R HL were recently published in the journal Clin Cancer Research.
The results showed that the carrelizumab monotherapy group was similar to The CR rates in the decitabine+carrelizumab combined treatment group were 32% and 79%, respectively.
Decitabine combined with immunotherapy can greatly improve the depth of remission of patients; there was no statistical difference between the two ORR groups
.

The DOR of the combination group was not reached; the DOR of the single-agent group was 12.
7 months
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In addition, the median PFS of the combination treatment group was 35 months, and that of the single-agent group was only 15.
5 months
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Combination therapy further improves the efficacy of PD-1 antibody in the treatment of R/R HL
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For patients with relatively large tumor burden, SPD ≥20 cm2, ≥30 cm2, or ≥50 cm2, the 2-year PFS rates of receiving decitabine + carrelizumab were 71%, 72%, and 67%, respectively
.

The median PFS of patients treated with carrelizumab alone (SPD≥20 cm2, ≥30 cm2, or ≥50 cm2) were 10 months, 12 months, and 11 months, respectively
.

Studies have shown that the remission rate has nothing to do with the size of the tumor, and large masses can still obtain good curative effects
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The SCENT study is a clinical study of Chidamide combined with Sintilizumab for R/R ENKTCL.
This study is the world's first use of PD-1 mAb combined with histone deacetylase for R/R ENKTCL population Inhibitor research
.

Of the 37 patients with evaluable efficacy, 22 (59.
4%) achieved objective remission, and 48.
6% achieved CR
.

The median DOR in the study was 13.
3+ months, and the combination therapy has significantly benefited patients
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It is also a study published on ASH in 2020.
The phase II study of pembrolizumab combined with romidepsin in the treatment of R/R TCL showed that the ORR reached 50% and the CR rate was 40%, especially from the study.
As a result, the expression of PD-L1 in CR patients is higher than that in PR or SD patients
.

2.
The cytotoxic effects of immune checkpoint inhibitors combined with chemotherapy/autologous hematopoietic stem cell transplantation chemotherapy drugs can cause tumor cell apoptosis, release neoantigens, and enhance tumor immunogenicity
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At the same time, chemotherapy drugs can also improve the immunosuppressive microenvironment of tumor cells through direct or indirect immune activation
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A study of PD-1 inhibitor monotherapy for sequential AVD chemotherapy was tried in newly treated cHL patients
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After PD-1 monotherapy, 11 patients (37%) had complete metabolic remission
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After 2 cycles of AVD chemotherapy, 100% of patients had complete metabolic remission, and the PFS rate and OS rate were 100%
.

In addition, in the second-line treatment, the PD-1 inhibitor combined with GVD was used for cHL.
The results showed that 95% of the 37 evaluable patients were evaluated as CR.
These patients were bridged to ASCT, and the median follow-up time after ASCT was 11.
2 Months, no case has progressed so far
.

In a phase II clinical study of carrelizumab combined with GVD in the treatment of R/R PMBCL by Professor Han Weidong’s team, the combined treatment had a significant effect with an ORR of 74.
1% and a CR rate of 55.
6%
.

It is worth noting that the study found that the lower the number of treatment lines in frontline patients, the higher the ORR; compared with patients with PD-L1 expression <30%, patients with PD-L1 expression ≥ 30% achieved CR more
.

In addition, the combination therapy can quickly reduce the tumor burden, with a median TTR of 1.
7 months, 78% of patients with tumor shrinkage at the first assessment, and the median PFS of the combination therapy group reached 15.
4 months, and the patients were well tolerated
.

3.
The study of immune checkpoint inhibitor combined with monoclonal antibody/antibody conjugate drug CheckMate 436 showed that in R/R PMBCL patients, the ORR evaluated by the investigator of nivolumab combined with BV treatment reached 70%, and the CR rate was 43 %
.

PD-1 inhibitors combined with BV can produce a certain synergistic effect, and this program has been included in the NCCN guidelines
.

The first-line standard immunochemotherapy for follicular lymphoma has significant efficacy but significant toxicity.
75% of patients experience grade 3-5 AEs, mainly infection and bone marrow suppression
.

There is an urgent need for a treatment plan with significant curative effect and low toxicity
.

The concept of "priming" the immune system with nivolumab before targeted tumor therapy is reasonable and evidence-based
.

Therefore, in this year's ICML meeting, a Nivolumab "immune priming", sequential Nivolumab and Rituximab first-line treatment of follicular lymphoma phase II study has brought some good clinical inspiration
.

Studies have shown that this chemotherapy-free regimen has lower toxicity and higher ORR and CR, and may be used as an alternative to chemotherapy
.

4.
The combination of immune checkpoint inhibitor and CAR-T can express PD-L1 on the surface of tumor cells and inhibit the activity of CAR-T cells, which becomes one of the reasons for the failure of CART
.

Compared with normal people, the expression of PD-1 in lymphoma patients' T cells is significantly higher
.

The use of PD-1 inhibitors is expected to enhance the killing activity of CAR-T cells.
The best timing and effectiveness of PD-1 monoclonal antibody and CAR-T are the direction of clinical trials
.

Previous studies have shown that PD-1/PD-L1 expression in some patients with diffuse large B-cell lymphoma is up-regulated after CAR-T treatment
.

An updated analysis of the Phase Ib PORTIA study of Tisagenlecleuce+Pembrolizumab in the treatment of R/R DLBCL patients showed that according to local assessments, the ORR of all patients receiving Tisagenlecleuce infusion was 50% (CR: 33.
3% and PR: 16.
7%)
.

The limited data at the date of this data indicate that the combination therapy is feasible and safety is manageable, and there is no clinically significant deterioration of DLTs or Tisagenlecleuce-related AEs
.

Regardless of the number or time of pembrolizumab administration, no signs of secondary amplification or re-accumulation of Tisagenlecleuce after pembrolizumab administration were observed
.

But the joint plan needs more exploration in the future
.

Summary Although PD-1 monoclonal antibody has shown a certain effect on a variety of lymphoma subtypes, there is still room for improvement in the remission rate, especially the CR rate
.

Combination therapy is the development direction of immunotherapy in the future
.

Epigenetics drugs can up-regulate the expression of PD-L1 in some tumor cells, suggesting that it may have synergy with PD-1 monoclonal antibody
.

PD-1 monoclonal antibody combined with decitabine in the treatment of cHL, combined with HDAC inhibitor in the treatment of T-cell lymphoma, initially showed a good effect
.

PD-1 monoclonal antibody and chemotherapy have a synergistic effect, and combined chemotherapy has an initial effect in cHL
.

PD-1 monoclonal antibody has exploratory value as a maintenance treatment after ASCT, and preliminary research results have been reported in cHL
.

Lymphoma diseases are highly heterogeneous.
The development of PD-1 monoclonal antibody combination therapy strategies in the future requires a combination of basic research and clinical trials to screen out patients and combinations that are most likely to benefit in order to optimize benefits
.

Professor Zhang Huilai Doctor of Oncology, Chief Physician, Doctoral Supervisor, Currently Director of Lymphoma Department of Cancer Hospital of Tianjin Medical University, Deputy Chairman of Lymphoma Professional Committee of Chinese Anti-Cancer Association, Chinese Society of Clinical Oncology (CSCO) Standing Committee of Anti-Lymphoma Alliance, China Healthcare Vice Chairman of the Oncology Branch of the International Exchange Promotion Association Vice Chairman of the Lymphoma Professional Committee of the Chinese Geriatric Healthcare Association Member of the Standing Committee of the Chinese Society of Clinical Oncology (CSCO) Oncology and Cardiology Committee Member of the Lymphoma Group of the Oncology Branch of the Chinese Medical Association Chinese Anti-Cancer Association Member of the Special Committee of Integrated Oncology and Cardiology, Chairman of the Lymphoma Professional Committee of Tianjin Anti-Cancer Association, Vice Chairman of Tianjin Blood Disease Quality Control Center, Vice Chairman of Tianjin Medical Doctor Association, Hematologist Branch, and we will make progress together.